Brougher Jackson, Aziz Umaymah, Adari Nikitha, Chaturvedi Muskaan, Jules Aryela, Shah Iqra, Syed Saba, Thorn Catherine A
Department of Neuroscience, University of Texas at Dallas, Richardson, TX, United States.
Front Neurosci. 2021 Dec 16;15:782786. doi: 10.3389/fnins.2021.782786. eCollection 2021.
Left cervical vagus nerve stimulation (l-VNS) is an FDA-approved treatment for neurological disorders including epilepsy, major depressive disorder, and stroke, and l-VNS is increasingly under investigation for a range of other neurological indications. Traditional l-VNS is thought to induce therapeutic neuroplasticity in part through the coordinated activation of multiple broadly projecting neuromodulatory systems in the brain. Recently, it has been reported that striking lateralization exists in the anatomical and functional connectivity between the vagus nerves and the dopaminergic midbrain. These emerging findings suggest that VNS-driven activation of this important plasticity-promoting neuromodulatory system may be preferentially driven by targeting the right, rather than the left, cervical nerve. To compare the effects of right cervical VNS (r-VNS) vs. traditional l-VNS on self-administration behavior and midbrain dopaminergic activation in rats. Rats were implanted with a stimulating cuff electrode targeting either the right or left cervical vagus nerve. After surgical recovery, rats underwent a VNS self-administration assay in which lever pressing was paired with r-VNS or l-VNS delivery. Self-administration was followed by extinction, cue-only reinstatement, and stimulation reinstatement sessions. Rats were sacrificed 90 min after completion of behavioral training, and brains were removed for immunohistochemical analysis of c-Fos expression in the dopaminergic ventral tegmental area (VTA) and substantia nigra pars compacta (SNc), as well as in the noradrenergic locus coeruleus (LC). Rats in the r-VNS cohort performed significantly more lever presses throughout self-administration and reinstatement sessions than did rats in the l-VNS cohort. Moreover, this appetitive behavioral responding was associated with significantly greater c-Fos expression among neuronal populations within the VTA, SNc, and LC. Differential c-Fos expression following r-VNS vs. l-VNS was particularly prominent within dopaminergic midbrain neurons. Our results support the existence of strong lateralization within vagal-mesencephalic signaling pathways, and suggest that VNS targeted to the right, rather than left, cervical nerve preferentially activates the midbrain dopaminergic system. These findings raise the possibility that r-VNS could provide a promising strategy for enhancing dopamine-dependent neuroplasticity, opening broad avenues for future research into the efficacy and safety of r-VNS in the treatment of neurological disease.
左侧颈迷走神经刺激（l-VNS）是一种经美国食品药品监督管理局（FDA）批准用于治疗包括癫痫、重度抑郁症和中风在内的神经系统疾病的方法，并且l-VNS正越来越多地被用于一系列其他神经适应症的研究。传统的l-VNS被认为部分通过大脑中多个广泛投射的神经调节系统的协同激活来诱导治疗性神经可塑性。最近，有报道称迷走神经与多巴胺能中脑之间的解剖和功能连接存在明显的偏侧化。这些新发现表明，VNS驱动的这个重要的促进可塑性的神经调节系统的激活可能优先通过靶向右侧而非左侧颈神经来驱动。为了比较右侧颈迷走神经刺激（r-VNS）与传统l-VNS对大鼠自我给药行为和中脑多巴胺能激活的影响。将大鼠植入靶向右侧或左侧颈迷走神经的刺激袖带电极。手术恢复后，大鼠进行VNS自我给药试验，其中杠杆按压与r-VNS或l-VNS给药配对。自我给药后进行消退、仅线索恢复和刺激恢复试验。行为训练完成后90分钟处死大鼠，取出大脑进行免疫组织化学分析，以检测多巴胺能腹侧被盖区（VTA）、黑质致密部（SNc）以及去甲肾上腺素能蓝斑核（LC）中c-Fos的表达。r-VNS组的大鼠在整个自我给药和恢复试验中的杠杆按压次数显著多于l-VNS组的大鼠。此外，这种食欲性行为反应与VTA、SNc和LC内神经元群体中显著更高的c-Fos表达相关。r-VNS与l-VNS后c-Fos表达的差异在多巴胺能中脑神经元中尤为突出。我们的结果支持迷走神经-中脑信号通路中存在强烈的偏侧化，并表明靶向右侧而非左侧颈神经的VNS优先激活中脑多巴胺能系统。这些发现增加了r-VNS可能为增强多巴胺依赖性神经可塑性提供一种有前景的策略的可能性，为未来研究r-VNS治疗神经系统疾病的疗效和安全性开辟了广阔的途径。
